Benzylimidazolyl substituted 2-quinoline and quinazoline derivatives for use as farnesyl transferase inhibitors

ABSTRACT

This invention comprises the novel compounds of formula (I)  
                 
 
wherein r, t, Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 6 and R 7  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

The present invention is concerned with novel (phenyl)methylimidazolylsubstituted 2-quinolinone and quinazolinone derivatives, the preparationthereof, pharmaceutical compositions comprising said novel compounds andthe use of these compounds as a medicine as well as methods of treatmentby administering said compounds.

Oncogenes frequently encode protein components of signal transductionpathways, which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes are frequently associated with human cancer. A particulargroup of oncogenes is known as ras, which have been identified inmammals, birds, insects, mollusks, plants, fungi and yeasts. The familyof mammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyze thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumors. Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumors in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinoline derivatives, which exhibit farnesyl transferaseinhibiting activity. WO 00/39082 describes a class of novel1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linkedimidazole, which show farnesyl protein transferase and geranylgeranyltransferase inhibiting activity. Other quinolinone compounds havingfarnesyl transferase inhibiting activity are described in WO 00/12498,WO 00/12499, WO 00/47574 and WO 01/53289.

WO97/36876 describes compounds with farnesyl transferase inhibitingactivity. The actual teaching of this publication is limited tocompounds of general formula

In this application, quinolinone and quinazolinone derivatives are notspecifically disclosed.

Unexpectedly, it has been found that the present novel compound, havinga phenyl substituent on the 4-position of the quinolinone moiety bearingthe (phenyl)methylimidazolyl substituent, show farnesyl proteintransferase inhibiting activity. The present compounds can haveadvantagous properties with regard to solubility and stability.

The present invention concerns compounds of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein

-   -   r is 0, 1, 2, 3;    -   t is 0, 1 or 2;    -   v is 0, 1 or 2;    -   >Y¹-Y²-is a trivalent radical of formula        >C═N—  (y-1),        >C═CR⁸—  (y-2),        >CH—NR⁸—  (y-3), or        >CH—CHR⁸—  (y-4),        -   wherein R⁸ is hydrogen, halo, cyano, C₁₋₆alkyl or hydroxy            carbonyl;    -   R¹ is hydrogen, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,        —(CR¹⁶R¹⁷)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹,        trihalomethyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,        C₁₋₆alkyloxyC₁₋₆alkyloxy, trihalomethoxy, C₂₋₆alkenyl,        C₂₋₆alkynyl, —CHO, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        —CONR¹⁸R¹⁹, mono- or di(C₁₋₆ alkyl)aminoC₁₋₆alkyloxy,        aminoC₁₋₆alkyloxy, —CR¹⁵═N—OR¹⁶;    -   two R¹ substituents adjacent to one another on the phenyl ring        may form together a bivalent radical of formula        —O—CH₂—O—  (a-1),        —O—CH₂—CH₂—O—  (a-2),        —O—CH═CH—  (a-3), or        —O—CH₂—CH₂—  (a-4),        -   wherein R¹⁵ and R¹⁶ are independently hydrogen or C₁₋₆            alkyl;        -   R¹⁷, R¹⁸ and R¹⁹ are independently hydrogen, C₁₋₄alkyl,            hydroxy or C₁₋₄alkyloxy;        -   p is 0 or 1    -   R² is hydrogen, halo, cyano, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, trifluoromethyl, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, nitro, cyanoC₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, —CHO, —CR²⁰═N—OR²¹;        -   R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl;    -   or two R² substituents adjacent to one another on the phenyl        ring may form together a bivalent radical of formula        —O—CH₂—O—  (a-1), or        —O—CH₂—CH₂—O—  (a-2);    -   R³ is hydrogen, hydroxy, halo, C₁₋₆alkyl, haloC₁₋₆alkyl,        cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-CONR¹⁸R¹⁹, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, carbonylC₁₋₆alkyl,        hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl or Het¹ or        -   a radical of formula            —O—R⁹   (b-1),            —NR¹⁰R¹¹   (b-2), or            —N═CR⁹R¹⁰   (b-3),        -   wherein R⁹ is hydrogen, C₁₋₆alkyl or a radical of formula            -Alk-OR¹² or -Alk-NR¹³R¹⁴;        -   R¹⁰ is hydrogen or C₁₋₂alkyl;        -   R¹¹is hydrogen, hydroxy, C₁₋₆alkyl,            —(CR¹⁶R¹⁷)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy,            C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,            arylC₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl,            C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl,            aminocarbonylcarbonyl, Het¹C₁₋₆alkylcarbonyl,            C₁₋₆alkylaminocarbonyl,        -   mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical            of formula -Alk-OR¹² or Alk-NR¹³R¹⁴;            -   wherein Alk is C₁₋₆alkanediyl;        -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl or            hydroxyC₁₋₆alkyl;        -   R¹³ is hydrogen, C₁₋₆alkyl or C₁₋₆alkylcarbonyl;        -   R¹⁴ is hydrogen, C₁₋₆alkyl or C₁₋₆alkylcarbonyl;    -   R⁴ is hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl or C₁₋₆alkyloxy;    -   R⁵ is hydrogen, C₁₋₁₂alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R¹⁵, aminocarbonylC₁₋₆alkyl-,        —C₁₋₆alkyl-OR¹⁵, —C₁₋₆alkyl-SR¹⁵, trifluoromethyl, Ar¹C₁₋₆alkyl,        Het¹C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        —C₁₋₆alkyl-NR²⁰R²¹;    -   R⁶ is oxygen or R⁵ and R⁶ together form a trivalent radical of        formula:        —CH═CH—N═  (x-1),        —CH═N—N═  (x-2), or        —N═N—N═  (x-3);    -   R⁷ is hydrogen or C₁₋₆alkyl or R³ and R⁷ together with the        carbon atom to which they are linked, form a radical of formula        C(O);        -   Ar¹ is phenyl or phenyl substituted by one to five            substituents each independently selected from halo, hydroxy,            amino, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy,            OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy,            C₁₋₆alkylsulfonylamino or phenyl;        -   Het¹ is a mono- or bi-cyclic heterocyclic ring containing            one or more heteroatoms selected from oxygen, sulphur and            nitrogen and optionally substituted by one or two            substituents each independently selected from halo, hydroxy,            cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁵R¹⁶,            C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,            —CONR¹⁵R¹⁶, —NR¹⁵R¹⁶, C₁₋₆alkylsulfonylamino or phenyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl2-methyl-butyl, 2-methylpentyl and the like; C₁₋₁₂ alkyl encompasses thestraight and branched chained saturated hydrocarbon radicals as definedin C₁₋₆alkyl as well as the higher homologues thereof containing 7 to 12carbon atoms such as, for example heptyl, octyl, nonyl, decyl, undecyl,dodecyl and the like; C₁₋₆alkanediyl defines bivalent straight andbranched chained saturated hydrocarbon radicals having from 1 to 6carbon atoms, such as, for example, methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and thebranched isomers thereof; haloC₁₋₆alkyl defines C₁₋₆alkyl containing oneor more halo substituents for example trifluoromethyl; C₂₋₆alkenyldefines straight and branched chain hydrocarbon radicals containing onedouble bond and having from 2 to 6 carbon atoms such as, for example,ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, and the like; C₂₋₆alkynyl defines straight andbranched chain hydrocarbon radicals containing one triple bond andhaving from 2 to 6 carbon atoms such as, for example, ethynyl,2-propynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, andthe like; aryl defines phenyl, naphthalenyl, phenyl substituted with oneor more substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl; or naphtalenylsubstituted with one or more substituents each independently selectedfrom halo, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano orhydroxycarbonyl; C₃₋₁₀cycloalkyl includes cyclic hydrocarbon groupshaving from 3 to 10 carbons, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl and the like.

Pharmaceutically acceptable addition salts encompass pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts. The pharmaceutically acceptable acid addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid addition salt forms that the compounds of formula (I) areable to form. The compounds of formula (I) which have basic propertiescan be converted in their pharmaceutically acceptable acid additionsalts by treating said base form with an appropriate acid. Appropriateacids comprise, for example, inorganic acids such as hydrohalic acids,e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric andthe like acids; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic(i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The term “acid or base addition salts” also comprises the hydrates andthe solvent addition forms, which the compounds of formula (I) are ableto form. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms, which saidcompound might possess. Said mixture may contain all diastereomersand/or enantiomers of the basic molecular structure of said compound.All stereochemically isomeric forms of the compounds of formula (I) bothin pure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -   a) r is 0 or 1;    -   b) t is 0 or 1;    -   c) v is 0 or 1;    -   d) >Y¹-Y²-is a trivalent radical of formula (y-1) or (y-2)        wherein R⁵ is hydrogen;    -   e) R¹ is halo, C₁₋₆alkyl or C₁₋₆alkyloxy;    -   f) R² is halo, cyano or two R² substituents adjacent to one        another on the phenyl ring may form together a bivalent radical        of formula (a-1);    -   g) R³ is hydrogen, cyanoC₁₋₆alkyl, —C₁₋₆alkyl-CONH₂, Het¹ or a        radical of formula (b-1) or (b-2) wherein R⁹ is hydrogen, R¹⁰ is        hydrogen or C₁₋₆alkyl and R¹¹ is hydrogen, hydroxy or C₁₋₆alkyl;    -   h) R⁴ is hydrogen;    -   i) R⁵ is C₁₋₁₂alkyl;    -   j) R⁶ is oxygen or R⁵ and R⁶ together form a trivalent radical        of formula (x-3);    -   k) R⁷ is hydrogen.

Another group of interesting compounds consists of those interestingcompounds of formula (I) wherein one or more of the followingrestrictions apply:

-   -   a) r is 1;    -   b) t is 0 or 1;    -   c) v is 0;    -   d) p is 0 or 1;    -   e) >Y¹-Y²-is a trivalent radical of formula (y-2) wherein R⁸ is        hydrogen;    -   f) R¹ is halo;    -   g) R² is hydrogen, halo or cyano;    -   h) R³is Het¹ or a radical of formula (b-1) or (b-2) wherein R⁹        is hydrogen or C₁₋₆alkyl, R¹⁰ is hydrogen and R¹¹ is hydrogen,        —(CH₂)—C₃₋₁₀cycloalkyl or C₁₋₆alkylcarbonyl;    -   i) R⁴ is hydrogen;    -   i) R⁵ is hydrogen, C₁₋₁₂alkyl, —(CR²OR² )_(p)—C₃₋₁₀cycloalkyl or        Ar¹C₁₋₆alkyl;    -   k) R is oxygen or R⁵ and R⁶ together form a trivalent radical of        formula (x-3);    -   l) R⁷is hydrogen, C₁₋₆alkyl or R³ and R⁷ together with the        carbon atom to which they are linked, form a radical of formula        C(O).

A further group of interesting compounds consists of those interestingcompounds of formula (I) wherein one or more of the followingrestrictions apply:

-   -   a) R¹ is 3-chloro or 3-bromo;    -   b) R² is 4-cyano;    -   c) R³is hydroxy;    -   d) R⁵is methyl.

A more interesting group of compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   -   a) r is 1;    -   b) t is 0 or 1;    -   c) v is 0;    -   d) p is 0;    -   e) >Y¹-Y²-is a trivalent radical of formula (y-2) wherein R⁸ is        hydrogen;    -   f) R¹ is halo;    -   g) R² is hydrogen or cyano;    -   h) R³is a radical of formula (b-1) or (b-2) wherein R⁹is        hydrogen, R¹⁰ is hydrogen and R¹¹ is hydrogen or        C₁₋₆alkylcarbonyl;    -   i) R⁴ is hydrogen;    -   i) R⁵ is C₁₋₁₂alkyl;    -   k) R⁶ is oxygen or R⁵ and R⁶ together form a trivalent radical        of formula (x-3);    -   l) R⁷ is hydrogen.

Another group of more interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen or C₁₋₆alkyl.

Preferred compounds are those compounds of formula (I) wherein r is 1; tis 0 or 1; v is 0; p is 0 or 1; >Y¹-Y²-is a trivalent radical of formula(y-2) wherein R⁸ is hydrogen; R¹ is halo; R² is hydrogen, halo or cyano;R³ is Het¹ or a radical of formula (b-1) or (b-2) wherein R⁹ is hydrogenor C₁₋₆alkyl, R¹⁰ is hydrogen and R¹¹ is hydrogen, —(CH₂)—₃₋₁₀cycloalkylor C₁₋₆alkylcarbonyl; R⁴ is hydrogen; R⁵ is hydrogen, C₁₋₁₂alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl or Ar¹C₁₋₆alkyl; R⁶ is oxygen or R⁵ andR⁶ together form a trivalent radical of formula (x-3); R⁷is hydrogen,C₁₋₆alkyl or R³ and R⁷ together with the carbon atom to which they arelinked, form a radical of formula C(O);

More preferred compounds are those compounds of formula (I) wherein r is1; t is 0 or 1; v is 0; p is 0; >Y¹-Y²-is a trivalent radical of formula(y-2) wherein R⁸ is hydrogen; R¹ is halo; R² is hydrogen or cyano; R³ isa radical of formula (b-1) or (b-2) wherein R⁹ is hydrogen, R¹⁰ ishydrogen and R¹¹ is hydrogen or C₁₋₆alkylcarbonyl; R⁴ is hydrogen; R⁵ isC₁₋₁₂alkyl; R⁶ is oxygen or R⁵ and R⁶ together form a trivalent radicalof formula (x-3); R⁷is hydrogen.

Most preferred compound are4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile(compound 3), compound 14 and compound 5.

The compounds of formula (I) and their pharmaceutically acceptable saltsand N-oxides and stereochemically isomeric forms thereof may beprepared, for example, by the following processes:

-   -   a) Intermediates of formula (II), in which W represents a        reactive group and A represents C₁₋₆alkyl, preferably methyl,        can react with an intermediate of formula (III) to form        intermediates of formula (IV). This reaction can be performed in        a reaction-inert solvent, such as, for example, tetrahydrofuran        in the presence of a strong base, such as, butyl lithium at a        temperature ranging from −70° C. to room temperature.        Intermediates of formula (IV) can be further hydrolysed under        acid conditions with the formation of quinolinones of        formula (I) wherein R⁵ is hydrogen and R³ is hydroxy, herein        referred to as compounds of formula (I-a).    -   b) Intermediates of formula (V), in which W represents a        reactive group can react with an intermediate of formula (III)        to form intermediates of formula (VI). This reaction can be        performed in a reaction-inert solvent, such as, for example,        tetrahydrofuran in the presence of a strong base such as butyl        lithium at a temperature ranging from −70° C. to room        temperature. Intermediates of formula (VI) can be further        converted into quinolinones of formula (I) in which R⁵ and R⁶        together form a trivalent radical of formulae (x-3) herein        referred to as compounds of formula (I-b-a) and (I-b-b). This        reaction can be performed through ring closure with sodiumazide        in a reaction inert solvent such as dimethylformamide at a        temperature of 90° C.    -   c) Intermediates of formula (VII) can react with an intermediate        of formula (III) to form intermediate ketones of formula (IX).        This reaction can be performed in a reaction-inert solvent, such        as, for example, tetrahydrofuran at a temperature from −70° C.        Said reaction requires the presence of a suitable strong base,        such as, for example, butyl-lithium in an appropriate silane        derivative, such as, for example, triethylchlorosilane.        Intermediates of formula (IX) can be further hydrolysed in the        presence of a suitable acid, such as HCl. After hydrolysis these        intermediates can be further reduced with an appropriate        reducing agent such as sodiumborohydride in the. presence of a        suitable solvent such as methanol, with the formation of        quinazolinones of formula (I) wherein R⁵ is hydrogen and R³ is        hydroxy, herein referred to as compounds of formula (I-c).    -   d) Intermediate ketones of formula (IX) can also be reduced with        an appropriate reducing agent, such as, sodiumborohydride in the        presence of a suitable solvent, such as, methanol. These        intermediates can then further be converted into quinazolinones        of formula (I) in which R⁵ and R⁶ together form a trivalent        radical of formula (x-3) herein referred to as compounds of        formulae (I-d). This reaction can be performed through ring        closure with sodiumazide in a reaction inert solvent, such as,        dimethylformamide at a temperature of 90° C.    -   e) Intermediates of formula (X), in which W represents a        reactive group and A represents C₁₋₆alkyl preferably methyl, can        react with an intermediate of formula (XI) to form intermediates        of formula (XII). This reaction requires the administration of        carbon monoxide at atmospheric pressure or increased pressure,        in the presence of a suitable palladium-catalyst (e.g. palladium        on charcoal), in the presence of a suitable solvent, such as,        for example, dioxolane and in the presence of a suitable base,        such as, tri ethyl amine. Intermediates of formula (XII) in        which A represents C₁₋₆alkyl preferably methyl can be further        converted into intermediates of formula (VII) in the presence of        a suitable oxidant such as phosphorylchloride in an appropriate        solvent such as dimethylformamide.    -   f) Intermediated ketones of formula (IX) can be converted into        compounds of formula (I-k), defined as a compound of formula (I)        wherein R³ is hydroxy and R⁷ is C₁₋₆alkyl by art-known        C₁₋₆-alkyl addition reactions.    -   g) Intermediate compounds of formula (VI) can be further        converted into intermediate ketones of formula (VIII) in the        presence of a reagent such as MnO2 and a suitable solvent such        as dioxane. These intermediate ketones of fomula (VIII) can be        further converted in intermediate ketones of formula (XIII) in        which A represents C₁₋₆alkyl, preferably methyl. This reaction        can be performed in the presence of a suitable solvent such as        MeOB in the presence of a suitable reagent such as CH₃ONa/MeOH        30%. Intermediate ketones of formula (XIII) can be further        hydrolysed in the presence of a suitable acid, such as HCl to        give compounds of formula (I-l).

Compounds of formula (I-a), (I-b-a), (I-b-b), (I-c), (I-d), (I-k) and(I-l) can optionally be the subject of one or more of the followingconversions in any desired order:

-   -   (i) converting a compound of formula (I) into a different        compound of formula (I);    -   (ii) converting a compound of formula (I) into the corresponding        acceptable salt or N-oxide thereof;    -   (iii) converting a pharmaceutically acceptable salt or N-oxide        of a compound of formula (I) into the parent compound of formula        (I);    -   (iv) preparing a stereochemical isomeric form of a compound of        formula (I) or a pharmaceutically acceptable salt or N-oxide        thereof.

Examples of the conversion of one compound of formula (I) into adifferent compound of formula (I) include the following reactions:

-   -   a) Compounds of formula (I-e) wherein R³ is hydroxy and R⁵ is        hydrogen, can be converted into compounds of formula (I-f),        defined as a compound of formula (I) wherein R³ is hydroxy and        R⁵ is C₁₋₆alkyl by art-known N-alkylation reactions, such as        treatment with an alkylhalogenide (e.g. iodomethane) in a        reaction inert solvent (e.g. tetrahydrofuran) optionally in the        presence of a base, such as, for example sodium hydroxide.    -   b) Compounds of formula (I-g) wherein R³ is hydroxy, can be        converted into compounds of formula (I-h), defined as a compound        of formula (I) wherein R is hydrogen, by submitting the        compounds of formula (I-g) to appropriate reducing conditions,        such as, e.g. treatment with sodium borohydride/trifluoroacetic        acid.    -   c) Compounds of formula (I-g) can be converted to compounds of        formula (I-i) wherein R³ is halo, by reacting the compounds of        formula (I-g) with a suitable halogenating agent, such as, e.g.        thionyl chloride or phosphorus tribromide. Successively, the        compounds of formula (I-i) can be treated with a reagent of        formula H—NR¹⁰R¹¹ in a reaction-inert solvent thereby yielding        compounds of formula (I-j).    -   d) Alternatively compounds of formula (I-g) can be converted        into compounds of formula (I-j), by treatment with acetic acid        ammonium salt at a temperature ranging from 120 to 180° C., or        by treatment with sulfamide at a temperature ranging from 120 to        180° C.    -   e) Compounds of formula (I) in which >Y¹-Y² represents a radical        of formula (y-1) or (y-2) can be converted into corresponding        compounds of formula (I) in which >Y¹-Y² represents a radical of        formula (y-3) or (y-4) respectively by conventional reduction        procedures, for example, hydrogenation or reduction by treatment        with sodium borohydride in a suitable solvent, e.g. methanol and        vice versa by conventional oxidation procedures such as, for        example, treatment with bromine in an appropriate solvent such        as, e.g. bromobenzene, or treatment with iodine in the presence        of acetic acid and potassium acetate.    -   f) The compounds of formula (I) may also be converted into each        other via art-known reactions or functional group        transformations. A number of such transformations are already        described hereinabove. Other examples are hydrolysis of        carboxylic esters to the corresponding carboxylic acid or        alcohol; hydrolysis of amides to the corresponding carboxylic        acids or amines; hydrolysis of nitriles to the corresponding        amides; amino groups on imidazole or phenyl may be replaced by a        hydrogen by art-known diazotation reactions and subsequent        replacement of the diazo-group by hydrogen; alcohols may be        converted into esters and ethers; primary amines may be        converted into secondary or tertiary amines; double bonds may be        hydrogenated to the corresponding single bond; an iodo radical        on a phenyl group may be converted in to an ester group by        carbon monoxide insertion in the presence of a suitable        palladium catalyst.

The intermediates and starting materials used in the above-describedprocesses may be prepared in conventional manner using procedures knownin the art for example as described in the above-mentioned patentspecifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO00/39082.

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers, which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they have a potent farnesyl proteintransferase (FPTase) inhibitory effect.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma and includingnon-small cell lung cancer), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), prostate cancer including theadvanced disease, hematopoietic tumors of lymphoid lineage (e.g. acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloidleukemias (for example, acute myelogenous leukemia (AML)), thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymalorigin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas,teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin(e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer),kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermalcarcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneuro-fibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compound according to the invention can be used for othertherapeutic purposes, for example:

-   -   a) the sensitisation of tumors to radiotherapy by administering        the compound according to the invention before, during or after        irradiation of the tumor for treating cancer, for example as        described in WO 00/01411;    -   b) treating athropathies such as rheumatoid arthritis,        osteoarhritis, juvenile arthritis, gout, polyarthritis,        psoriatic arthritis, ankylosing spondylitis and systemic lupus        erythematosus, for example as described in WO 00/01386;    -   c) inhibiting smooth muscle cell proliferation including        vascular proliferative disorders. atherosclerosis and        restenosis, for example as described in WO 98/55124;    -   d) treating inflammatory conditions such as ulcerative colitis,        Crohn's disease, allergic rhinilis, graft vs host disease,        conjunctivitis, asthma, ARDS, Behcets disease, transplant        rejection, uticaria, allergic dermatitis, alopecia areata,        scieroderma, exanthem, eczema, dermatomyositis, acne, diabetes,        systemic lupus erythematosis, Kawasaki's disease, multiple        sclerosis, emphysema, cystic fibrosis and chronic bronchitis;    -   e) treating endometriosis, uterine fibroids, dysfunctional        uterine bleeding and endometrial hyperplasia;    -   f) treating ocular vascularisation including vasculopathy        affecting retinal and choroidal vessels;    -   g) treating pathologies resulting from heterotrimeric G protein        membrane fixation including diseases related to following        biological functions or disorders; smell, taste, light,        perception, neurotransmission, neurodegeneration, endocrine and        exocrine gland functioning, autocrine and paracrine regulation,        blood pressure, embryogenesis, viral infections, immunological        functions, diabetes, obesity;    -   h) inhibiting viral morphogenesis for example by inhibiting the        prenylation or the post-prenylation reactions of a viral protein        such as the large delta antigen of hepatitis D virus; and the        treatment of HIV infections;    -   i) treating polycystic kidney disease;    -   j) suppressing induction of inducible nitric oxide including        nitric oxide or cytokine mediated disorders, septic shock,        inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;    -   k) treating malaria.

The compounds of present invention may be particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

For the treatment of the above conditions, the compound of the inventionmay be advantageously employed in combination with one or more othermedicinal agents such as anti-cancer agents for example selected fromplatinum coordination compounds for example cisplatin or carboplatin,taxane compounds for example paclitaxel or docetaxel, camptothecincompounds for example irinotecan or topotecan, anti-tumor vincaalkaloids for example vinblastine, vincristine or vinorelbine,anti-tumor nucleoside derivatives for example 5-fluorouracil,gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylatingagents for example cyclophosphamide, chlorambucil, carmustine orlomustine, anti-tumor anthracycline derivatives for exampledaunorubicin, doxorubicin or idarubicin; HER2 antibodies for exampletrastzumab; and anti-tumor podophyllotoxin derivatives for exampleetoposide or teniposide; and antiestrogen agents including estrogenreceptor antagonists or selective estrogen receptor modulatorspreferably tamoxifen, or-alternatively toremifene, droloxifene, faslodexand raloxifene, or aromatase inhibitors such as exemestane, anastrozole,letrazole and vorozole.

For the treatment of cancer the compounds according to the presentinvention can be administered to a patient as described above, inconjunction with irradiation. Such treatment may be especiallybeneficial, as farnesyl transferase inhibitors can act asradiosensitisers, for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumor by radionuclidescan be external or internal.

Preferably, the administration of the farnesyl transferase inhibitorcommences up to one month, in particular up to 10 days or a week, beforethe irradiation of the tumor. Additionally, it is advantageous tofractionate the irradiation of the tumor and maintain the administrationof the farnesyl transferase inhibitor in the interval between the firstand the last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumor, its location, thepatient's reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumor comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a        farnesyl protein transferase inhibitor according to the        invention before, during or after    -   administering radiation to said host in the proximity to the        tumor.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate-the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calcuated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.005mg/kg to 100 mg/kg body weight, and in particular from 0.5 mg/kg to 100mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, and in particular 10 mg to500 mg of active ingredient per unit dosage form.

The following examples are provided for purposes of illustration.

Hereinafter “THF” means tetrahydrofuran, “EtOAc” means ethyl acetate,and “BuLi” means n-butyl lithium, “DIPE” means diisopropyl ether, “DCM”means dichloromethane, “iPrOH means isopropyl ether and “MeOH“meansmethanol.

A. PREPARATION OF THE INTERMEDIATES EXAMPLE A1

a) Sodium hydroxide (0.62 mol) was dissolved in methanol (100 ml) andthe mixture was cooled till room temperature. 1-Bromo-4-nitro-benzene(0.124 mol), followed by 3-chloro-benzeneacetonitrile (0.223 mol) wasadded dropwise, the temperature rose till 50° C. and the mixture wasstirred at room temperature for one night. The mixture was poured intowater and ice, the precipitate was filtered off, washed with water andextracted with DCM and methanol. The organic layer was dried (MgSO₄),filtered off and evaporated till dryness. The residue was taken up indiethylether, filtered off and dried, yielding 13.2 g (34.8%) of5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole, mp. 163° C. (intermediate1).

b) TiCl₃/15% water (1050 ml) was added at room temperature to a solutionof intermediate 1 (0.386 mol) in THF (1350 ml) and the mixture wasstirred at room temperature for 2 h. The mixture was poured into waterand ice and extracted with DCM. The organic layer was decanted, washedwith K₂CO₃ 10%, dried (MgSO₄), filtered off and evaporated, yielding 102g (85%) of (2-amino-5-bromophenyl)(3-chlorophenyl)-methanone(intermediate 2).

c) A solution of intermediate 2 (0.328 mol) and acetic acid anhydride(0.656 mol) in toluene (1200 ml) was stirred and refluxed for one night.The mixture was evaporated and the product was used without furtherpurification, yielding 139 g (quant.) ofN-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).

d) 2-Methyl-2-propanol, potassium salt (1.635 mol) was added portionwiseat room temperature to a solution of intermediate 3 (0.328 mol) in1,2-dimethoxyethane (1200 ml) and the mixture was stirred at roomtemperature for one night. The mixture was evaporated till dryness, theresidue was poured into water and ice and decanted. The oily residue wastaken up in DIPE, the precipitate was filtered off, washed with EtOAc,acetonitrile and diethyl ether and dried, yielding 88.6 g (80.76%) of6-bromo-4-(3-chlorophenyl)-2(1H)-quinolinone (intermediate 4).

e) A mixture of intermediate 4 (0.16 mol) in phosphoryl chloride (500ml)was stirred and refluxed for one night. The mixture was evaporated tilldryness, the residue was taken up in ice and water, alkalized with NH₄OHand extracted with DCM. The organic layer was decanted, dried (MgSO₄),filtered off and evaporated, yielding 56 g (100%) of6-bromo-2-chloro-4-(3-chlorophenyl)quinoline, mp.125° C. (intermediate5).

f) CH₃ONa 30%/methanol (96 ml) was added to a solution of intermediate 5(0.16 mol) in methanol (500 ml) and the mixture was stirred and refluxedfor one night. The mixture was evaporated till dryness. The residue wastaken up in DCM, washed with water and decanted. The organic layer wasdried (MgSO₄), filtered off and evaporated. The residue was taken up indiethylether and DIPE, the precipitate was filtered off and dried,yielding 48 g (86%) of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline,mp. 124° C. (intermediate 6).

g) BuLi (0.0226 mol) was added to a solution of intermediate 6 (0.0206mol) in THF (70 ml), under N₂ flow, at −70° C. The mixture was stirredat −70° C. for 15 minutes. A solution of4-[(5-formyl-1H-imidazol-1-yl)methyl]-benzonitrile (0.0226 mol) in THF(50 ml) was added at −70° C. The mixture was stirred at −70° C. for 1hour, brought to room temperature and stirred 1 hour at thistemperature. The mixture was poured out into ice water, extracted withEtOAc. The organic layer was separated, washed with water, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (15-40 μm) (eluent:DCM/MeOH/NH₄OH 97/3/01). The pure fractions were collected and thesolvent was evaporated, yielding 0.5 g (5%) of3-(3-chlorophenyl)-N-[4-[[1-[(4-cyanophenyl)methyl]-1H-imidazol-5-yl]hydroxymethyl]phenyl]-2-propenimidicacid (1E,2E)-methyl ester (intermediate 7).

EXAMPLE A2

Preparation of

This experiment was performed twice on the same quantities. BuLi 1.6M inhexane (0.0027 mol) was added at −70° C. to a solution of6-bromo-2-chloro4-(3-chlorophenyl)-quinoline (0.0024 mol) in THF (10 ml)under N₂ flow. The mixture was stirred at −70° C. for 1 hour. A solutionof 1-[(4-chlorophenyl)methyl]-1H-imidazole-5-carboxaldehyde (0.0026 mol)in THF (7 ml) was added at −70° C. The mixture was stirred at −70° C.for 1 hour, then at room temperature overnight, poured out into icewater and extracted with EtOAc. The organic layer was washed with water,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(2.7 g) was purified by column chromatography over silica gel (15-40 μm)(eluent: DCM/MeOH/NH₄OH 97/3/0.2 to 95/5/0.1). The pure fractions werecollected and the solvent was evaporated, yielding 0.38g (16%) ofintermediate 8.

EXAMPLE A3

a) Preparation of

BuLi 1.6M in hexane (0.0167 mol) was added at -78° C. to a solution of6-bromo-2-chloro4-(3-chlorophenyl)-quinoline (0.0152 mol) in THF (30ml)under N₂ flow. The mixture was stirred at −78° C. for 1 hour. A solutionof 1-(phenylmethyl)-1H-imidazole-5-carboxaldehyde (0.0167 mol) in THF(20 ml). was added at −78° C. The mixture was stirred at −78° C. for 1hour, then at room temperature for 5 hours. Water was added. The mixturewas extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (7.8 g)was taken up in DCM/MeOH and crystallized from DIPE. The precipitatewas filtered off and dried, yielding 0.67 g (9%) of intermediate 9. Thefiltrate was evaporated. The residue (6.96 g) was purified by columnchromatography over silica gel (15-40 μm ) (eluent: DCM/MeOH/NH₄OH95/5/0.2). The pure fractions were collected and the solvent wasevaporated, yielding 1.4 g (8%) of intermediate 9.b) Preparation of

Manganese oxide (0.0014 mol) was added to a mixture of intermediate 9(0.0014 mol) in dioxane (10 ml). The mixture was stirred and refluxedfor 5 hours, then cooled to room temperature, filtered over celite. Thefiltrate was evaporated, yielding 0.66 g (99%) of intermediate 10,melting point 89° C.c) Preparation of

MeOH (10 ml) was added at 5° C. to intermediate 10 (0.0024 mol).MeONa/MeOH 30% (0.0097 mol) was added dropwise at 5° C. The mixture wasbrought to room temperature, stirred and refluxed for 5 hours, thencooled. The precipitate was filtered off and dried, yielding 0.74 g(67%) of intermediate 11. The filtrate was taken up in DCM, washed withwater and extracted with DCM. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated, yielding 0.35 g (31%)of intermediate 11, melting point 143° C.

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B1

A mixture of intermediate 7 (0.94 mol) in HCl 3N (5 ml) was stirred atreflux overnight, cooled at room temperature and poured out into icewater. DCM and methanol (little quantity) were added. The organic layerwas basified by K₂CO₃, separated, dried over MgSO₄, filtered, and thesolvent was evaporated, yielding 0.44 g of4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile(compound 1).

EXAMPLE B2

Sodium hydroxide 1N (2 ml), N,N,N-triethylbenzenemethanaminium chloride(0.282 mol) then iodomethane (0.94 mol) were added to a solution ofcompound 1 (0.94 mol) in THF (2 ml). The mixture was stirred at roomtemperature overnight, poured out into ice water and extracted withEtOAc. The organic layer was separated, washed with water, dried (MSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH₄OH93/7/01). Two fractions were collected and the solvent was evaporated,yielding 0.033 g (7%) of 4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl2-oxo-6-quinolinyl]methoxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile(compound 2) and 0.15 g (33%) F2. F2 was crystallized fromCH₃CN/diethylether. The precipitate was filtered off and dried, yielding0.12 g (27%) of4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile(compound 3), melting point 150° C.

EXAMPLE B3

Preparation of

This experiment was performed twice on the same quantities. A mixture ofintermediate 8 (0.0002 mol) and sodium azide (0.0005 mol) in DMF (10 ml)was stirred at 140° C. overnight. Water was added. The mixture wasextracted with DCM. The organic layer was washed several times withwater, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidues of the two experiments were combined (0.196 g) and werepurified by column chromatography over silica gel (10 μm) (eluent:DCM/MeOH 98/2 to 95/5). Two fractions were collected and the solvent wasevaporated, yielding 0.043 g F1 and 0.05 g F2. F1 was taken up in DCM.The precipitate was filtered, washed with diethyl ether and dried,yielding 0.041 g (20%) of compound 4, melting point 105° C. F2 was takenup in DCM/MeOH. The precipitate was filtered, washed with diethyl etherand dried, yielding 0.041 g (20%) of compound 5, melting point 140° C.

EXAMPLE B4

Preparation of

HCl 3N (6 ml) was added to a solution of intermediate 11 (0.0007 mol) inTHF (3 ml). The mixture was stirred at 60° C. for 5 hours, poured outinto ice water, basified with NH₄OH. The precipitate was filtered offand dried, yielding 0.358 g (>100%) of compound 6.

EXAMPLE B5

Preparation of

Iodomethane (0.0049 mol) was added to a mixture of compound 6 (0.0024mol) and benzyltriethylammonium chloride (0.0012 mol) in THF (11 ml) andNaOH 10N (11 ml). The mixture was stirred at room temperature for 6hours. Water was added. The mixture was extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (0.953 g, 84%) was crystallized fromDCM/diethyl ether. The precipitate was filtered off and dried, yielding0.55 g of compound 7, melting point 192° C.

EXAMPLE B6

Preparation of

Sodium tetrahydroborate (0.0026 mol) was added at 5° C. to a mixture ofcompound 7 (0.0012 mol) in THF (3 ml) and MeOH (3 ml) under N₂ flow. Themixture was stirred at 5° C. for 2 hours. Ice and water were added. Themixture was extracted with EtOAc. The organic layer was separated, dried(MgSO4), filtered, and the solvent was evaporated, yielding 0.551 g(100%) of compound 8, melting point 188° C.

EXAMPLE B7

a) Preparation of

A mixture of compound 8 (0.0001 mol) in thionyl chloride (0.6 ml) wasstirred at room temperature for 2 hours. The solvent was evaporated tilldryness, yielding 0.065 g of intermediate 12. This product was useddirectly in the next reaction step.b) Preparation of

Cyclopropanamine (0.0023 mol) was added to a mixture of intermediate 12(0.0001 mol) in acetonitrile (2 ml). The mixture was stirred andrefluxed for 5 hours. Water was added. The mixture was extracted withDCM. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (0.047 g) was purified by columnchromatography over silica gel (10 μm) (eluent: DCM/MeOH/NH₄OH 98/2/0.1to 95/5/0.1). The pure fractions were collected and the solvent wasevaporated, yielding 0.016 g (25%) of compound 9.

EXAMPLE B8

Preparation of

A mixture of intermediate 12 (0.0005 mol) in NH₃/MeOH 7N (2.7 ml) wasstirred at room temperature for 4 hours, poured out into ice water andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (0.242 g) waspurified by column chromatography over silica gel (10 μm) (eluent:DCM/MeOH/NH₄OH 96/4/0.1). Two fractions were collected and the solventwas evaporated, yielding 0.042 g F1 and 0.026 g F2. F1 was purified bycolumn chromatography over silica gel (10 μm) (eluent: DCM/MeOH/NH₄OH98/2/0.1). The pure fractions were collected and the solvent wasevaporated, yielding 0.016 g (6%) of compound 10. F2 was purified bycolumn chromatography over silica gel (10 μm) (eluent: DCM/MeOH/NH₄OH92/8/0.2). The pure fractions were collected and the solvent wasevaporated, yielding 0.01 g (4%) of compound 11.

EXAMPLE B9

Preparation of

A mixture of compound 8 (0.0001 mol) and 1,1′-carbonyldiimidazole(0.0003 mol) in ThF (2 ml) was stirred and refluxed for 24 hours.1,1′-carbonyldiimidazole (0.0001 mol) was added. The mixture was stirredand refluxed for 2 days, then cooled to room temperature. THF wasevaporated. The residue was taken up in DCM. The organic layer waswashed with K₂CO₃ 10%, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.1 g) was purified by column chromatographyover silica gel (10 μm) (eluent: toluene/iPrOH/NH₄OH 90/10/0.1). Thepure fractions were collected and the solvent was evaporated, yielding0.045 g (56%) of compound 12, melting point 102° C.

EXAMPLE B 10

Preparation of

Sulfuric acid concentrated (2 drops) were added to a solution ofcompound 8 (0.0002 mol) in acetonitrile (1 ml). The mixture was stirredand refluxed for 24 hours. Water was added. The mixture was basifiedwith NH₄OH and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(0.09 g) was purified by column chromatography over silica gel (10 μm)(eluent: toluene/iPrOH/NH₄OH 85/15/0.2). The pure fractions werecollected and the solvent was evaporated. The residue (0.053 g) wascrystallized from DCM/DIPE. The precipitate was filtered off and dried,yielding 0.03 g (38%) of compound 13, melting point 210° C. TABLE F-1Table F-1 lists the compounds that were prepared according to one of theabove Examples. The following abbreviations were used in the tables:Co.No. stands for Compound Number, Ex. [Xn°] referred to the same methodas described in the Xn° example.

Co. No. 1; Ex. [B1]

Co. No. 2; Ex. [B2]

Co. No. 3; Ex. [B2]; mp. 150° C.

Co. No. 4; Ex. [B3]; mp. 105° C.

Co. No. 5; Ex. [B3]; mp. 140° C.

Co. No. 14; Ex. [B3]; mp. 158° C.

Co. No. 6; Ex. [B4]; MH⁺ 440, 442 mp. ° C.

Co. No. 15; Ex. [B4]; mp. 255° C.

Co. No. 7; Ex. [B5]; mp. 192° C.

Co. No. 16; Ex. [B5]; mp. 122° C.

Co. No. 17; Ex. [B5]; mp. 214° C.

Co. No. 8; Ex. [B6]; mp. 188° C.

Co. No. 9; Ex. [B7]

Co. No. 10; Ex. [B8]; MH⁺ 470, 472 mp. ° C.

Co. No. 11; Ex. [B8]; MH⁺ 455, 457

Co. No. 12; Ex. [B9]; mp. 102° C.

Co. No. 13; Ex. [B10]; mp. 210° C.

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 “In Vitro Assay for Inhibition ofFarnesyl Protein Transferase”

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33-34. Herein the effectsof test compounds are expressed as pIC₅₀ (the negative log value of theIC₅₀-value) and as % of inhibition at 10⁻⁷ M.4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile(compound 3) has a pIC₅₀ of 8.3 and compound 14 has a pIC₅₀ of 7.968

EXAMPLE C.2 “Ras-Transformed Cell Phenotype Reversion Assay”

The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3 “Farnesyl Protein Transferase Inhibitor Secondary TumorModel”

The farnesyl protein transferase inhibitor secondary tumor model wasused as described in WO 98/40383, page 37. TABLE F-2 Table F-2 lists theresults of the compounds that were tested according to example C.1.Enzyme % of activity inhibition Co. No. pIC50 at 10⁻⁷ M 14 7.968 87 5 <732 4 <7 26 16 <7 18 17 <7 33 12 <7 47 13 >7 65 9 <7 44 10 <7 43 11 <7 493 8.264 92

D. COMPOSITION EXAMPLE Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere is added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein r is 0, 1, 2, 3; t is 0, 1 or 2; v is 0,1 or 2; >Y¹-Y²-is a trivalent radical of formula>C═N—  (y-1),>C═CR⁸—  (y-2),>CH—NR⁸—  (y-3), or>CH—CHR⁸—  (y-4), wherein R⁸ is hydrogen, halo, cyano, C₁₋₆alkyl orhydroxy carbonyl; R¹ is hydrogen, hydroxy, halo, cyano, nitro,C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹,trihalomethyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, trihalomethoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,—CHO, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, mono- ordi(C₁₋₆ alkyl)aminoC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, —CR¹⁵═N—OR¹⁶; two R¹substituents adjacent to one another on the phenyl ring may formtogether a bivalent radical of formula—O—CH₂—O—  (a-1),—O—CH═CH—  (a-3), or—O—CH₂—CH₂—  (a-4), wherein R¹⁵ and R¹⁶ are independently hydrogen orC₁₋₆ alkyl; R¹⁷, R¹⁸ and R¹⁹ are independently hydrogen, C₁₋₄alkyl,hydroxy or C₁₋₄alkyloxy; p is 0 or 1; R² is hydrogen, halo, cyano,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, trifluoromethyl,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, nitro, cyanoC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, —CR²⁰═N—OR²¹; R²⁰ and R²¹ areindependently hydrogen or C₁₋₆ alkyl; or two R² substituents adjacent toone another on the phenyl ring may form together a bivalent radical offormula—O—CH₂—O—  (a-1), or—O—CH₂—CH₂—O—  (a-2); R³ is hydrogen, hydroxy, halo, C₁₋₆alkyl,haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-CONR¹⁸R¹⁹,mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, carbonylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl orHet¹ or a radical of formula—O—R⁹   (b-1),—NR¹⁰R¹¹   (b-2), or—N═CR⁹R¹⁰   (b-3), wherein R⁹ is hydrogen, C₁₋₆alkyl or a radical offormula -Alk-OR¹² or -Alk-NR¹³R¹⁴; R¹⁰ is hydrogen or C₁₋₁₂alkyl; R¹¹ ishydrogen, hydroxy, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)—C₃₋₁₀cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,arylC₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, aminocarbonylcarbonyl,Het¹ C₁₋₆alkylcarbonyl, C₁₋₆alkylaminocarbonyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula -Alk-OR¹²or Alk-NR¹³R¹⁴; wherein Alk is C₁₋₆alkanediyl; R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl or hydroxyC₁₋₆alkyl; R¹³ is hydrogen,C₁₋₆alkyl or C₁₋₆alkylcarbonyl; R¹⁴ is hydrogen, C₁₋₆alkyl orC₁₋₆alkylcarbonyl; R⁴ is hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl orC₁₋₆alkyloxy; R⁵ is hydrogen, C₁₋₁₂alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R¹⁵,aminocarbonylC₁₋₆alkyl-, —C₁₋₆alkyl-OR¹⁵, —C₁₋₆alkyl-SR¹⁵,trifluoromethyl, Ar¹ C₁₋₆alkyl, Het¹ C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl-NR²⁰R²¹; R⁶ is oxygen or R⁵ and R⁶together form a trivalent radical of formula:—CH═CH—N═  (x-1),—CH═N—N═  (x-2), or—N═N—N═  (x-3); R⁷ is hydrogen, C₁₋₆alkyl or R³ and R⁷ together with thecarbon atom to which they are linked, form a radical of formula C(O);Ar¹ is phenyl or phenyl substituted by one to five substituents eachindependently selected from halo, hydroxy, amino, cyano, nitro,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aryloxy, C₁₋₆alkylsulfonylamino or phenyl; Het¹ isa mono- or bi-cyclic heterocyclic ring containing one or moreheteroatoms selected from oxygen, sulphur and nitrogen and optionallysubstituted by one or two substituents each independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁵R¹⁶,C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁵R¹⁶,—NR¹⁵R¹⁶, C₁₋₆alkylsulfonylamino or phenyl.
 2. A compound according toclaim 1 wherein r is 1; t is 0 or 1; v is 0; >Y¹-Y²-is a trivalentradical of formula (y-2) wherein R⁸ is hydrogen; R¹ is halo; R² is,hydrogen, halo or cyano; R³ is Het¹ or a radical of formula (b-1) or(b-2) wherein R⁹ is hydrogen or C₁₋₆alkyl, R¹⁰ is hydrogen and R¹¹ ishydrogen, —(CH₂)—C₃₋₁₀cycloalkyl or C₁₋₆alkylcarbonyl; R⁴ is hydrogen;R⁵ is hydrogen, C₁₋₁₂alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl or Ar¹C₁₋₆alkyl; R⁶ is oxygen or R⁵ and R⁶ together form a trivalent radicalof formula (x-3); R⁷ is hydrogen, C₁₋₆alkyl or R³ and R⁷ together withthe carbon atom to which they are linked, form a radical of formulaC(O);
 3. A compound according to claim 1 in which r is 1; t is 0 or 1; vis 0; >Y¹-Y²-is a trivalent radical of formula (y-2) wherein R⁸ ishydrogen; R¹ is halo; p is 0; R²is hydrogen or cyano; R³ is a radical offormula (b-1) or (b-2) wherein R⁹ is hydrogen, R¹⁰ is hydrogen and R¹¹is hydrogen or C₁₋₆alkylcarbonyl; R⁴ is hydrogen; R⁵ is C₁₋₁₂alkyl; R⁶is oxygen or R⁵ and R⁶ together form a trivalent radical of formula(x-3); R⁷ is hydrogen.
 4. A compound selected from the group consistingof compound 3, compound 14 and compound 5:


5. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier, and as active ingredient a therapeutically effective amount ofa compound as described in claim
 1. 6. (canceled)
 7. (canceled) 8.(canceled)
 9. (canceled)
 10. A process for the preparation of a compoundas claimed in claim 1 which comprises: a) reacting an intermediate offormula (V), in which W represents a reactive group, with anintermediate of formula (II) to form intermediates of formula (VI) andfurther converting the intermediates of formula (VI) into quinolinonesof formula (I) in which R⁵ and R⁶ together form a trivalent radical offormulae (x-3) herein referred to as compounds of formulae (I-b-a) and(I-b-b)

b) reacting an intermediate of formula (VII) with an intermediate offormula (III) to form intermediate ketones of formula (IX) and furtherhydrolysis of the intermediate ketones of formula (IX) in the presenceof a suitable acid followed by a reduction with an appropriate reducingagent, with the formation of quinazolinones of formula (I) wherein R⁵ ishydrogen and R³ is hydroxy, herein referred to as compounds of formula(I-c)

c) reducing intermediate ketones of formula (IX) with an appropriatereducing agent and further converting these intermediates intoquinazolinones of formula (I) in which R⁵ and R⁶ together form atrivalent radical of formulae (x-3) herein referred to as compounds offormulae (I-d)

d) optionally effecting one or more of the following conversions in anydesired order: (i) converting a compound of formula (I) into a differentcompound of formula (I); (ii) converting a compound of formula (I) intothe corresponding acceptable salt or N-oxide thereof; (iii) converting apharmaceutically acceptable salt or N-oxide of a compound of formula (I)into the parent compound of formula (I); (iv) preparing a stereochemicalisomeric form of a compound of formula (I) or a pharmaceuticallyacceptable salt or N-oxide thereof.